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Review
. 2022 Jul 21;27(14):4660.
doi: 10.3390/molecules27144660.

Potential Natural Biomolecules Targeting JAK/STAT/SOCS Signaling in the Management of Atopic Dermatitis

Spandana Rajendra Kopalli  1 , Venkata Prakash Annamneedi  2 , Sushruta Koppula  3
Affiliations
Review

Potential Natural Biomolecules Targeting JAK/STAT/SOCS Signaling in the Management of Atopic Dermatitis

Spandana Rajendra Kopalli et al. Molecules. .

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin disease caused by the dysregulation of cytokines and other immune mediators. JAK/STAT is a classical signal transduction pathway involved in various biological processes, and its dysregulation contributes to the key aspects of AD pathogenesis. Suppressor of cytokine signaling (SOCS) proteins negatively regulate the immune-related inflammatory responses mediated by the JAK/STAT pathway. JAK/STAT-mediated production of cytokines including IL-4, IL-13, IL-31, and TSLP inhibits the expression of important skin barrier proteins and triggers pruritus in AD. The expression of SOCS proteins regulates the JAK-mediated cytokines and facilitates maintaining the skin barrier disruptions seen in AD. STATs are crucial in dendritic-cell-activated Th2 cell differentiation in the skin, releasing inflammatory cytokines, indicating that AD is a Th2-mediated skin disorder. SOCS proteins aid in balancing Th1/Th2 cells and, moreover, regulate the onset and maintenance of Th2-mediated allergic responses by reducing the Th2 cell activation and differentiation. SOCS proteins play a pivotal role in inflammatory cytokine-signaling events that act via the JAK/STAT pathway. Therapies relying on natural products and derived biomolecules have proven beneficial in AD when compared with the synthetic regimen. In this review, we focused on the available literature on the potential natural-product-derived biomolecules targeting JAK/STAT/SOCS signaling, mainly emphasizing the SOCS family of proteins (SOCS1, SOCS3, and SOCS5) acting as negative regulators in modulating JAK/STAT-mediated responses in AD pathogenesis and other inflammatory disorders.

Keywords: JAK-STAT pathway; SOCS proteins; atopic dermatitis; cytokines; interleukins; natural biomolecules.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chemical structures of selected natural compounds targeting SOCS expression and JAK/STAT-signaling pathways.
Figure 2
Figure 2
Schematic diagram of selected natural biomolecules and their possible target sites in JAK/STAT/SOCS signaling in AD pathogenesis. Pathogenic microbes, allergens, and environmental toxins often attack the skin, accelerating inflammation by releasing cytokines, which are activated by antigen presenting cells, leading to AD. Antigen-presenting cells activate naïve Th0 cells, making them mature and differentiate into Th2 cells. TH2 cells release cytokines, leading to activation of the JAK/STAT pathway in stimulated mast cells and further enhancing the release of inflammatory cytokines, which are causative factors for various allergic diseases including AD. The cytokines released cause pruritus and skin barrier dysfunction, thereby increasing the severity of AD. Simultaneously, the negative regulators of JAK/STAT signaling, namely SOCS proteins (SOCS1, 3, and 5), are activated to block STAT phosphorylation to control excessive cytokine-mediated skin damage. Possible involvement of selected natural biomolecules at target sites through inhibiting the cytokine release via Th2 cells or enhancing the expression of SOCS proteins, thereby negatively regulating activation of JAK/STAT signaling in the management of AD pathogenesis, is shown.
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